The primary functions of the kidneys are to rid the body of metabolic and ingested waste products and to maintain the volume and composition of body fluids. The kidneys perform these functions by filtering the blood through the glomerular capillaries into the renal tubules. As the filtrate passes down the tubules, its composition is altered as substances are selectively reabsorbed back into the non-filtered blood in the peritubular capillaries that surround the tubules. Substances may also be selectively secreted from the tubules into the peritubular capillary blood. After these processes of tubular reabsorption and tubular secretion have taken place, the resulting filtrate is excreted as urine.
The maintenance of a constant extracellular fluid (ECF) volume by the kidneys is accomplished by various neural, hormonal, and intrinsic homeostatic mechanisms that control the rate at which blood is filtered by the glomeruli, referred to as the glomerular filtration rate (GFR), and the extent to which sodium and water are reabsorbed from the filtrate into the peritubular capillary blood. The body defends against changes in both arterial pressure and ECF volume by controlling GFR and the tubular reabsorption of sodium and water in response to changes in arterial blood pressure. The kidneys then produce a volume of urine as appropriate to cause the body to excrete or retain water. One of these homeostatic mechanisms is the renin-angiotensin-aldosterone system (RAAS). A decrease in arterial blood pressure (and/or a decrease in plasma osmolarity) causes juxtaglomerular cells in the kidney to release renin into the blood. Renin is an enzyme that converts a circulating protein called angiotensinogen into angiotensin I, the latter then being enzymatically converted into angiotensin II. Angiotensin II is a very potent vasoconstrictor that constricts blood vessels in many areas of the body to raise peripheral resistance and arterial pressure. Angiotensin II also causes the kidneys to retain sodium and water in several ways that include: 1) causing the adrenal glands to secrete aldosterone, which then acts on the renal tubules to increase sodium and water reabsorption, 2) causing constriction of renal arterioles to diminish renal blood flow and GFR, and 3) acting directly on the renal tubules to increase tubular reabsorption of sodium and water. The opposite effects occur when blood pressure rises.
Another homeostatic mechanism is pressure natriuresis, which refers to the intrinsic response of the kidneys when renal arterial pressure increases to increase urinary excretion of sodium and water. When renal arterial pressure rises, renal blood flow and GFR increase which increases the amount of tubular fluid. Also, increased renal arterial pressure raises the hydrostatic pressure in the peritubular capillaries and the renal interstitium which reduces the reabsorption of sodium and water from the tubules. Both of these effects thus result in an increased volume of urine when renal arterial pressure rises and vice-versa.
The kidneys also receive extensive sympathetic innervation and respond to changes in sympathetic activity. Baroreceptors, such as those in the aortic arch and carotid sinus, activate the sympathetic nervous system in response to a decrease in arterial blood pressure. Increased sympathetic activity decreases sodium and water excretion in several ways that include: 1) constricting the renal arterioles to decrease renal blood flow and GFR, 2) acting on the renal tubules to increase reabsorption of sodium and water, and 3) stimulating the release of renin.
The kidneys normally act so as to maintain both arterial blood pressure and ECF volume within desired normal ranges. In certain pathological situations, however, the homeostatic mechanisms discussed above do not respond in an appropriate manner to maintain blood pressure and/or ECF volume within normal ranges. For example, the intrinsic autoregulation of GFR by the kidney is often impaired in kidney disease causing a greater than normal pressure natriuresis. In some patients with hypertension, on the other hand, the pressure natriuresis mechanism may be impaired so that the kidneys do not excrete adequate amounts of salt and water unless arterial pressure becomes abnormally high. Hypertension may also result from the renal response to increased sympathetic activity.
Another situation in which the homeostatic mechanisms of the kidneys may not respond in an optimal manner is during heart failure (HF), which refers to a clinical syndrome in which an abnormality of cardiac function causes a below normal cardiac output that can fall below a level adequate to meet the metabolic demand of peripheral tissues. HF can be due to a variety of etiologies with ischemic heart disease being the most common. When heart failure occurs acutely, such as from a myocardial infarction (MI), sympathetic circulatory reflexes are activated that both increase the contractility of the heart and constrict the vasculature as the body tries to defend against the drop in blood pressure. Venous constriction, along with the reduction in the heart's ability to pump blood out of the venous and pulmonary systems (so-called backward failure), causes an increase in the diastolic filling pressure of the ventricles. This increase in preload (i.e., the degree to which the ventricles are stretched by the volume of blood in the ventricles at the end of diastole) causes an increase in stroke volume during systole, a phenomena known as the Frank-Starling principle. If the heart failure is not too severe, this compensation is enough to sustain the patient at a reduced activity level. When moderate heart failure persists, other compensatory mechanisms come into play that characterize the chronic stage of heart failure. The most important of these is the depressing effect of a low cardiac output on renal function due to decreased renal perfusion, which causes a reduction in salt and water excretion by the pressure natriuresis mechanism. The increased sympathetic activity in response to low blood pressure and/or cardiac output may also depress renal function still further. The increased fluid retention by the kidneys results in an increased blood volume and further increased venous return to the heart, thus increasing the heart's preload. A state of compensated heart failure results when the factors that cause increased diastolic filling pressure are able to maintain cardiac output at a normal level even while the pumping ability of the heart is compromised. If cardiac function worsens or increased cardiac output is required due to increased activity or illness, however, the compensation may not be able to maintain cardiac output at a level sufficient to maintain normal renal function. Fluid then continues to be retained by kidneys, causing the progressive peripheral and pulmonary edema that characterizes overt congestive heart failure. Diastolic filling pressure also becomes further elevated which causes the heart to become so dilated and edematous that its pumping function deteriorates even more. This condition, in which the heart failure continues to worsen while excess fluid accumulates in the lungs and extremities, is decompensated heart failure. It can be detected clinically, principally from the resulting pulmonary congestion and dyspnea, and can lead to rapid death unless appropriate therapy is instituted.
Even if acute decompensation does not occur, persistent heart failure and accompanying fluid retention by the kidneys may result in a complex remodeling process of the ventricles that involves structural, biochemical, neurohormonal, and electrophysiologic factors. When the ventricles are stretched due to the increased preload over a period of time, the ventricles become dilated. As the heart begins to dilate, afferent baroreceptor and cardiopulmonary receptor signals are sent to the vasomotor central nervous system control center, which responds with hormonal secretion and sympathetic discharge. It is the combination of hemodynamic, sympathetic nervous system and hormonal alterations (such as presence or absence of angiotensin converting enzyme (ACE) activity) that ultimately account for the deleterious alterations in cell structure involved in ventricular remodeling. The sustained stresses caused by the increased loading induce apoptosis (i.e., programmed cell death) of cardiac muscle cells and eventual wall thinning which causes further deterioration in cardiac function. It has been shown that the extent of ventricular remodeling is positively correlated with increased mortality in post-MI and heart failure patients.
Modulation of renal function to improve the situations described above can be performed by pharmacological means. For example, in the treatment of hypertension, vasodilators can be used to increase renal blood flow, and diuretic drugs can be used to decrease the tubular reabsorption of salt and water. Such pharmacological agents are not always effective, however, and they are not without significant side effects.